PROJECT SUMMARY Alzheimer?s disease, a crippling disease of the aging polulation, shows a predilection for women, particularly after menopause . The biological basis of the higher incidence, more rapid progression, and enhanced symptom load in post?menopausal women, when compared with men of the same age, remains unclear. Declining estrogen levels have been implicated, but studies showing an early spike in incidence of Alzheimer?s neuropathology and cognitive impairment at a time when estrogen levels are relatively unperturbed makes this 1-5 possibility unlikely 6-12 . It is also notable that FSH levels rise during this perimenopausal phase, and changes in serum FSH have been implicated by us and others in the bone loss, visceral adiposity, and dysregulated energy metabolism that ensue8,9,13-16. Indeed, contrary to textbook physiology, wherein pituitary hormones, such as FSH, were assigned a single regulatory function, we discovered more ubiquitous actions of almost every pituitary hormone16-22. We have identified functional FSH receptors (FSHRs) on bone cells and adipocytes13,18, and, in preliminary data provided here, report receptors in several brain regions. In collaborative studies with Dr. Keqiang Ye (Emory), we also show that FSH given to 3xTg mice worsens the Alzheimer?s neuropathology and cognitive decline, and importantly, that our polyclonal antibody to a defined receptor?binding region of FSH? attenuates these changes. The question therefore is whether actions of FSH on the brain can contribute to cognitive deterioration, particularly when FSH levels are elevated. This question is in contextual alignment with U19 AG60917, in which we explore the actions of FSH, as an aging hormone, on bone and fat, as well as with PA?18?591 (NOT?AG?20?008), that seeks to extend the overall relevance of this work to Alzheimer?s disease. Thus, our goal for this yearlong supplement is to solidify our current preliminary data on the expression of FSHRs in brain regions (Specific Aim 1), contemporaneously reproduce neuropathological and behavioral datasets from the Emory lab that utilized our polyclonal anti?FSH? antibody, and examine the effect of our newly?developed humanized monoclonal antibody, Finskelzumab, in the 3xTg mouse (Specific Aim 2). Noting that Finskelzumab is currently in preclinical development for use in osteoporosis and obesity, it would be a monumental success story if its use could be extended to Alzheimer?s disease. Whether or not this is possible, we expect any new data to form the framework for a future R01 to probe the neural functions of FSH.